The proposed studies are directed toward defining cellular mechanisms of production of anti-Sm, an autoantibody found both in human and in murine systemic lupus erythematosus (SLE). Studies from this laboratory have indicated a key role for T cells in the regulation of anti-Sm production in MRL mice. Using an in vitro culture system to study spontaneous anti-Sm production, the nature and mechanism of action of these regulatory T cells will be established. Particular attention will be directed toward the antigen phenotype of the T cells, their requirements for accessory cells and Ia-encoded restriction elements, and their antigen specificity. The recognition by T cells of the Sm antigen will also be investigated using an antigen-specific proliferation assay developed in this laboratory. The nature of the antigenic determinants of Sm perceived by T cells will be determined, as well as the roles of macrophages, Ia antigens, and immune response genes in this response in SLE mice and in normals. Preliminary data indicate that the T-cell response to murine Sm is under MHC-linked genetic control, yet the SLE strain, MRL-Mp-+/+ is capable of recognition of Sm despite its nonresponder (H-2k) haplotype. This finding will be pursued by investigating the genetics of the Sm response of the T cells of these autoimmune mice. The fine specificity of T cell recognition of Sm will be determined by examining the reactivity of cloned T cells to Sm. Such cloned cells will also be used to determine the functional activity of Sm-specific T cells in regulation of anti-Sm production. The long-term objective of this investigation is to define the cellular mechanisms of production of the disease-specific autoantibody, anti-Sm, and thus to gain insight into the pathogenesis of SLE.